Summary: Translationally Controlled Tumor Protein (TCTP) is a master-regulator of tumorigenesis and tumor reversion process. Our preliminary studies showed that TCTP promotes survival of androgen-dependent prostate cancer cells under androgen deprived conditions by activating androgen receptor (AR) expression. Therefore, TCTP may be an important therapeutic target for castration-resistant prostate cancer (CRPC). The hypothesis of this proposal is that targeting TCTP will inhibit AR pro-survival signaling and promote cell death in CRPC cells. To address our hypothesis, in specific aim 1, we will determine whether targeting TCTP by Dihydroartemsinin (inhibitor of TCTP) and RNAi inhibits CRPC tumor growth in xenograft model of nude mice. In specific aim 2, we will identify the underlying anti-cancer mechanisms of targeting TCTP using in vitro models. In aim 1, we will determine whether targeting TCTP by RNAi inhibits androgen independent tumor growth of 22Rv1 cells in subcutaneous and orthotopic implantation model of nude mice. In parallel studies, we will also determine the combinatory therapeutic effects of Dihydroartemisinin and Enzalutamide in nude mice model of CRPC. Tumor samples collected from these mice will be subjected to histopathology and western blot and immunohistochemical analysis to determine the expression of TCTP, AR, PSA, GPX4, and PCNA. In aim 2, we will elucidate whether suppression of AR signaling and activation of whether ferroptosis as the potential underlying anti- cancer mechanism of targeting TCTP in CRPC cells. Lastly, our studies will also determine whether targeting TCTP eliminates resistance to Enzalutamide treatment. Conventional treatment strategies for AIPC are often ineffective. In this study, we will be employing variety of approaches such as gene silencing, pharmacological intervention, immunoprecipitation, flow cytometry, confocal, Western blot, and real-time PCR assays. The proposed studies will yield valuable molecular insights to help design TCTP as a novel therapeutic target for CRPC.